Day: September 22, 2023

Interview: “The Only Good TB Bacillus is a Dead One”, Says UCT’s Prof Valerie Mizrahi

By Biénne Huisman for Spotlight

Professor Valerie Mizrahi, a world-leading tuberculosis researcher and director of the Institute of Infectious Disease and Molecular Medicine at the University of Cape Town, is retiring at the end of the year. PHOTO: Nasief Manie/Spotlight

World-leading tuberculosis researcher Professor Valerie Mizrahi was 35 when her mother Etty started losing weight and coughing furiously. After healthcare professionals in Johannesburg failed to accurately diagnose her, it was a doctor in Plettenberg Bay who told Etty: “The good news is you don’t have lung cancer, the bad news is that you have tuberculosis (TB).”

At the time, Mizrahi’s two infant daughters – aged one and three years old – had been spending much time with their granny. And so Mizrahi found herself crushing TB prevention tablets into her children’s porridge with honey.

Etty was treated at the then-Rietfontein Hospital, the precursor to Sizwe Tropical Diseases Hospital in Johannesburg. “My mom got very ill,” recalls Mizrahi. “She almost died of TB. And then 10 years later, she had to have a lobe from one of her lungs removed because she was one of those unfortunate people who got post-TB fibrosis.”

This was the early 1990s. Mizrahi was then with the South African Institute for Medical Research (SAIMR) linked to the University of the Witwatersrand, where she established the Molecular Biology Unit. She had identified TB as a lurking problem in South Africa, particularly in mines and in hospitals, calling it “a worthy foe ripe with opportunity for scientific investigation” – a problem she felt not enough people were talking about. It had been a pivotal moment when TB entered her own home, one that she says galvanised her thinking.

“It was a dramatic eye-opener for me as a basic scientist,” she says. “It was traumatic because of the time it happened in my career. Our family suddenly being thrust into the world of TB control. We had all these questions like we didn’t know where my mum got it, was her TB drug-susceptible, and why it would take so long to find this out. I got to see first-hand how difficult it was to get answers…”

Born in 1958 to Etty and Morris in Harare, Zimbabwe, Mizrahi studied at the University of Cape Town (UCT), forging an unusual career path, veering from mathematics and chemistry to biochemistry, genetics, and microbiology. In a male-dominated field, she became one of the first in South Africa to interrogate TB at a basic science level – that is to say, research aimed at advancing our understanding of the basic science of how TB bacteria survive, replicate, and resist attempts to kill it.

‘the only good TB bacillus is a dead one’

Discussing TB, Mizrahi’s passion is effervescent, her every second sentence punctuated with “okay”. These underscore her statements – subtle pauses allowing for her preceding words to sink in.

Source: CC0

…there’s a reason why TB has persisted for so long. The bacillus is pretty hard to kill. It’s built like Fort Knox.

Prof Valerie Mizrahi

A particular interest for Mizrahi is developing antibiotics “that can kill this bacterium stone cold dead”.

“To me, the only good TB bacillus is a dead one,” she says. “But there’s a reason why TB has persisted for so long. The bacillus is pretty hard to kill. It’s built like Fort Knox. So it’s a monumental challenge. We don’t know where all the bacteria are residing. We know that TB in an infected lung is sitting in really difficult places, hard places for drugs to get to. This notion of going after the bacillus with drugs and just slamming it is a tough problem. Not insurmountable, but there’s a lot of research that needs to be done.”

TB can be cured, but treatment typically takes at least six months and involves taking at least four different antibiotics, with side effects ranging from minor to serious. In addition to research on new antibiotics, there are also several experimental TB vaccines currently in late-phase studies. The only TB vaccine we have was developed more than a century ago and only has some moderate efficacy in kids.

The IDM

Since 2011 Mizrahi has served as director of the Institute of Infectious Disease and Molecular Medicine (IDM) – the University of Cape Town’s (UCT) largest cross-faculty research unit with over 800 affiliated staff and grants running into hundreds of millions of rands.

Mizrahi’s glass-encased office looks directly onto Table Mountain and hospital bend – where, at the time of our interview, N2 traffic out of Cape Town is already at a standstill. Behind her desk, Mizrahi quips. “Yes, this is the most beautiful office at UCT, everyone agrees…” Below, students can be seen milling about on the health sciences campus.

Last year in its Best Global Universities 2022-2023 survey, online portal US News ranked UCT as 24th best university in the world for studying infectious diseases. Mizrahi is ambivalent about the IDM taking credit for this accolade. She notes that this success is founded on problems of a “confounding and overwhelming” scope, with many diseases being proxies for poverty and inequality in South Africa.

The IDM’s focus includes TB, HIV/AIDS, COVID-19, other infectious diseases like sexually transmitted infections, and non-communicable diseases such as preventable cancers, cardiovascular, and psychiatric disorders.

Reflecting on the IDM, she says they have accrued a “research ecosystem – a concentration of expertise, something resembling critical mass” – bringing together specialists across the basic, clinical, and public health sciences, in one place.

“We’ve got Groote Schuur Hospital across the road,” she says. “We have geneticists and biochemists, virologists, and immunologists. There’s a clinician across the corridor from me, bioinformaticians, and microscopists downstairs. If you are the kind of researcher who revels in asking questions and finding people who can answer them, then this is the place for you.”

Going forward, multi-disciplinary research is what excites her. “HIV and TB have been so dominant in the narrative of this country. But now when you look at the figures and the data, we are dealing with a huge burden of non-communicable disease on top of infectious diseases,” she says. “The key question moving forward is how not to think in silos.”

Polymaths and dilettantes

This, she says, takes humility.

“To do this, one has to be very humble. You need to know what you don’t know. People who work really well in interdisciplinary spaces are those who understand the limits of their own specialist knowledge, and the need to listen to where another person is coming from.”

She distinguishes between polymaths and dilettantes. “You have to be careful not to be a dilettante, who knows a little about a lot. Research can be very superficial in that way. So I have my antenna out all the time to distinguish between polymaths, who really are people who know a lot about a lot, and dilettantes who know a little about a lot. And well, in this institute we have a lot of polymaths, brilliant researchers who move across disciplines, very interesting people to work with.”

With a string of awards and an A1-rating from South Africa’s National Research Foundation, earlier this year, Mizrahi was elected a fellow of the Royal Society, the United Kingdom’s National Academy of Sciences. However, she recalls humbling moments along the way – like the time she flew to London seven months pregnant with her second child, for her first-ever interview with the Wellcome Trust committee to secure funding. “I was so confident, but I was ill-prepared,” she says. “They savaged me! I tried to frame it not as a failure but as a learning experience.”

Passing the baton

At the end of this year, Mizrahi will pass on the baton when she retires. Of her achievements, she is proudest of young scholars she has helped to shape. “Their legacies will last much longer than a few more citations of a publication,” she says.

Mizrahi notes more and more women leaders in her field. For example, recently, while delivering a talk at the Weizmann Institute in Israel, she noticed chemist and Nobel laureate Ada Yonath in the room. “Talk about a role model; I was almost in tears.”

Studying at UCT, Mizrahi’s own mentors had mostly been men – something she didn’t even notice, she says, as male professors treated her no different. What did cut her was racial segregation at the time, prompting a political awakening and stints leaving South Africa to work in the United States. First as a postdoctoral fellow at Pennsylvania State University and then at drug company, SmithKline & French in Philadelphia.

Her own background makes her sensitive to marginalised groups, she says. Her grandparents were Sephardi Jews who fled Rhodes Island, today part of Greece, ten years before World War II, to find refuge in Zimbabwe.

Having just read former UCT vice-chancellor Max Price’s book Statues and Storms: Leading a University Through Change, she says, “It took me back to some very difficult times. It’s harrowing and brave and made me realise that even though I was here in the midst of it [#feesmustfall and #rhodesmustfall protests], a senior person of the university, how little I really knew of what was going on. It really is a lesson in crisis leadership.”

 There’s no control experiment to life, you can’t go back and redo it.

Mizrahi lives in Sea Point with her one daughter. Her other daughter is based in Vancouver. Here, she likes to park her car at the end of the week, walking around – “either listening to a New York Times podcast or a beautiful piece of music and that’s when I think.”

She describes herself as an introvert who needs personal time to stay sane. She is deeply thoughtful about her roots, wondering about a sense of belonging. “As white people in Africa, I think this is part of the reckoning we go through. I truly identify as being African. Arriving at Johannesburg, just breathing in the air, it feels like home.”

Looking back, Mizrahi notes her mother as a major influence in her life. “Not a highly educated woman. But the wisest, smartest person I know.” Etty still lives in Johannesburg while Morris has passed away. To this day, Etty thinks of herself as a proud TB survivor, says Mizrahi.

On her retirement, the scholar says, “Now it’s about opening up opportunities for others, writing a few papers, and contributing to the TB drug discovery space.”

“I’ve done the best I can,” she says, “I don’t believe in having regrets…  There’s no control experiment to life, you can’t go back and redo it. But I don’t know that I could have done it any differently.”

Republished from Spotlight under a Creative Commons Licence.

Source: Spotlight

Discovery Group Posts Strong Year-end Growth in Profit

Presenting its financial year-end results to investors and analysts, Discovery Group has reported profit increases of 24% across all of its opertaions. CEO Adrian Gore commented, “Discovery’s three business composites – South Africa, United Kingdom and Vitality Global – delivered excellent performances in line with the Group’s strategy and ambition.”

For the reporting period, Discovery posted an increase in normalised profit from operations, up 24% from R9 384 million to R11 661 million. Headline earnings increased by 5% to R5 490 million; normalised headline earnings increased by 32% to R7 678 million; and core new business annual premium income (API) rose 12% to R22 788 million. Embedded value increased to R98 176 million, which represented a 13.2% return on embedded value.

In a year characterised by significant macroeconomic uncertainty, Discovery continued its focus on delivering quality earnings and cashflow with a strong balance sheet; while following a clear growth strategy for each composite (SA, UK and Vitality Global). The Group invested in its proprietary Vitality Shared-value model, and intensified the focus on key initiatives while closing business areas with marginal benefits.

The Group remained financially resilient with high levels of liquidity and the financial leverage ratio (FLR) improving to 20%. Organic cash generation was robust during the year following growth in quality earnings, a significant recovery in Discovery Life’s cash generation following elevated COVID-19-related claims in the previous reporting period, and the reduction in the cost of new initiatives. The robust balance sheet and cash positions support the resumption of dividends, and the directors declared a final gross cash dividend of 110 cents per ordinary share.

Discovery’s saw excellent results for each composite. The SA Composite’s normalised operating profit increased by 22% to R9 096 million and new business by 11% to R16 818 million. Discovery Health showed strong growth across all metrics with prior investment in technology driving efficiencies and continued innovation. Discovery Life had a resilient performance with positive variances, with Group Life returning to profit. Discovery Invest generated significant growth in profit, given higher investment markets and other in-period gains. Discovery Insure delivered on its profit turnaround, following actions taken in previous periods. Discovery Bank continued with excellent progress across all metrics, as acquisition of quality clients accelerated over the year.

Normalised operating profits rose by 14% for the UK Composite and 49% for Vitality Global (US$44 million), driven by especially strong results from China.

Gore concluded, “Discovery’s growth strategy is based on the efficacy, repeatability, and scalability of our Vitality Shared-value model. It is a powerful platform from which to drive new business and enables us to pursue growth through our organic businesses and global partnerships. The Group is now focused on evolving the model into an integrated value chain with bespoke modules to drive growth and market leadership across each of the composites.”

Strong Results from Methotrexate Trial for Severe Atopic Dermatitis in Kids

Atopic dermatitis in a young patient. Source: NIH

Positive results from a clinical trial comparing the safety and efficacy of ciclosporin with methotrexate in children and adolescents with severe dermatitis will likely change treatment paradigms for this debilitating skin condition, its researchers have said. The trial, published in the British Journal of Dermatology, also examined whether the severity of the disease changed or returned after treatment ended.

For children and young people with atopic dermatitis, the most common skin condition in children, the main first line conventional systemic treatments are methotrexate and ciclosporin, two immuno-modulatory drugs.

There have been no adequately powered randomised clinical trial evidence for safety and treatment success for paediatric patients with this condition, and with new therapies being introduced at a high cost, establishing a gold standard for treatment with the conventional systemic therapies like methotrexate and ciclosporin is needed.

The trial, led by King’s College London, assessed 103 children with severe atopic dermatitis age 2–16 years across 13 centres in the UK and Ireland. The patients were given oral doses of methotrexate or ciclosporin and assessed over nine months of treatment and six months after the therapy ended.

The study found that ciclosporin works faster and reduces disease severity more at 12 weeks but was more expensive, whereas methotrexate was significantly cheaper and led to better objective disease control after 12 weeks and off therapy, with fewer participant-reported flares of atopic dermatitis after treatment had stopped. There were also no concerning safety signals.

Based on the TREAT trial findings, methotrexate is a useful and safe treatment in paediatric patients with severe atopic dermatitis and a good alternative to ciclosporin, especially in settings where health care resources are limited.

Professor Carsten Flohr, Chair in Dermatology and Population Health Sciences at King’s College London, and consultant dermatologist at St John’s institute of dermatology, Guy’s and St Thomas’ NHS Foundation Trust, said:

“This is the largest paediatric trial using conventional immuno-modulatory treatments in severe atopic dermatitis and was conducted across 13 centres in the UK and Ireland and is likely to change our treatment paradigm around this condition, not just for patients in the UK but also internationally.”

Source: King’s College London

Activists Meet to Discuss Worsening Food Crisis for Children

Photo by Thought Catalog on Unsplash

A group of activists for food access and affordability met yesterday (Thursday 21 September 2023) to discuss the worsening food crisis for children. Convened by the Nelson Mandela Children’s Fund and the DG Murray Trust, the meeting sought to identify urgent measures to combat rising rates of severe acute malnutrition and child hunger.

The activist group includes representatives of COSATU, the South African Council of Churches, civil
society groups and academics. It endorsed the proposal by the DG Murray Trust and the Grow Great Zero-Stunting Campaign for government and the food industry to contribute equally in making at least one product label of ten highly nutritious foods far more affordable to poorer households. This proposal requests food manufacturers and retailers to ‘double discount’ a list of ten best buy foods, with the amount of profit waived by industry matched by a retail subsidy by government.

“Data from the Department of Health shows that there were over 15 000 cases of severe acute malnutrition requiring hospitalisation in the 2022/3 financial year,” says Dr Linda Ncube Nkomo, CEO of the Nelson Mandela Children’s Fund. “But that is just the tip of the iceberg”, she says. “Malnutrition is the underlying cause of about one-third of all child deaths in South Africa today, this despite Section 28 of the Constitution which guarantees the right of nutrition to every child”.

The problem of acute malnutrition worsens the chronically high levels of food insecurity in South Africa,
with over a quarter of children under five nutritionally stunted. Poor physical growth is just one manifestation of much deeper damage being done to the life-long wellbeing of children, not least to their brain development,” says Dr Edzani Mphaphuli, Executive Director of the Grow Great zero-stunting campaign. “If we don’t stop stunting now,” Mphaphuli continues, “we shouldn’t expect learning outcomes to improve or our economy to grow.”

In addition to the double-discounted basket of ten best buys, the group called on the food formula industry to stop extracting massive profits from the poorest mothers, whose own malnutrition makes breastfeeding difficult. Given the high cost of infant formula, desperate mothers water down the milk to make it stretch further, which means that their babies don’t get enough protein and vitamins. It also called on government to ensure that every province has an effective programme in place to identify children at high risk and to provide nutritional supplementation to children failing to thrive.

The group undertook to monitor food prices actively and to challenge the food industry to make the third of young children who live below the food poverty line their responsibility too. “We are heartened that NEDLAC has tasked a multi-sectoral committee to review the viability of proposal to double-discount ten best buy foods”, says Dr David Harrison, CEO of the DG Murray Trust. “No sector of society – not government, not labour, not civil society nor industry – should be able to say that substantive proposals to feed South Africa’s children are too difficult, without putting a better option on the table.”

Can We Predict the Severity of Food Allergies Using Genetics?

Photo by Sangharsh Lohakare on Unsplash

Researchers have discovered that a genetic biomarker may be able to help predict the severity of food allergy reactions. Currently there is no reliable or readily available clinical biomarker that accurately distinguishes patients with food allergies who are at risk for severe life-threatening reactions versus more mild symptoms. The researchers reported their findings in the Journal of Allergy and Clinical Immunology.

The researchers, led by Ann & Robert H. Lurie Children’s Hospital of Chicago, found that the presence of an enzyme isoform called α-tryptase, which is encoded by the TPSAB1 gene, correlates with increased prevalence of anaphylaxis or severe reaction to food as compared to subjects without any α-tryptase.

“Determining whether or not a patient with food allergies has α-tryptase can easily be done in clinical practice using a commercially available test to perform genetic sequencing from cheek swabs,” said lead author Abigail Lang, MD, MSc, attending physician and researcher at Lurie Children’s and Assistant Professor of Pediatrics at Northwestern University Feinberg School of Medicine. “If the biomarker is detected, this may help us understand that the child is at a higher risk for a severe reaction or anaphylaxis from their food allergy and should use their epinephrine auto-injector if exposed to the allergen. Our findings also open the door to developing an entirely new treatment strategy for food allergies that would target or block α-tryptase. This is an exciting first step and more research is needed.”

Tryptase is found mainly in mast cells, which become activated during allergic reactions. Increased TPSAB1 copy number which leads to increased α-tryptase is already known to be associated with severe reactions in adults with Hymenoptera venom allergy (or anaphylaxis following a bee sting).

Dr Lang’s study included 119 participants who underwent TPSAB1 genotyping, 82 from an observational food allergy cohort at the National Institute of Allergy and Infectious Diseases (NIAID) and 37 from a cohort of children who reacted to peanut oral food challenge at Lurie Children’s.

“We need to validate our preliminary findings in a much larger study, but these initial results are promising,” says Dr Lang. “We also still need a better understanding of why and how α-tryptase makes food allergy reactions more severe in order to pursue this avenue for potential treatment.”

Source: Ann & Robert H. Lurie Children’s Hospital of Chicago